SGLT2 Inhibitors and GLP-1 Receptor Agonists in Diabetic Kidney Disease: Evolving Evidence and Clinical Application - PubMed (original) (raw)

Review

SGLT2 Inhibitors and GLP-1 Receptor Agonists in Diabetic Kidney Disease: Evolving Evidence and Clinical Application

Jae Hyun Bae. Diabetes Metab J. 2025 May.

Abstract

Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease and significantly increases cardiovascular risk and mortality. Despite conventional therapies, including renin-angiotensin-aldosterone system inhibitors, substantial residual risk remains. The emergence of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists has reshaped DKD management. Beyond glycemic control, these agents provide distinct and complementary cardiorenal benefits through mechanisms such as hemodynamic modulation, anti-inflammatory effects, and metabolic adaptations. Landmark trials, including CREDENCE, DAPA-CKD, EMPA-KIDNEY, and FLOW, have demonstrated their efficacy in preserving kidney function and reducing adverse outcomes. SGLT2 inhibitors appear more effective in mitigating glomerular hyperfiltration and lowering heart failure risk, whereas GLP-1 receptor agonists are particularly beneficial in reducing albuminuria and atherosclerotic cardiovascular events. Although indirect comparisons suggest that SGLT2 inhibitors may offer greater protection against kidney function decline, direct head-to-head trials are lacking. Combination therapy holds promise, however further studies are needed to define optimal treatment strategies. This review synthesizes current evidence, evaluates comparative effectiveness, and outlines future directions in DKD management, emphasizing precision medicine approaches to enhance clinical outcomes. The integration of these therapies represents a paradigm shift in diabetes care, expanding treatment options for people with diabetes mellitus at risk of kidney failure.

Keywords: Diabetes mellitus; Diabetic nephropathies; Glucagon-like peptide-1 receptor agonists; Renal insufficiency, chronic; Sodium-glucose transporter 2 inhibitors.

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Conflict of interest statement

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

Figures

Fig. 1.

Fig. 1.

Pathophysiology of diabetic kidney disease and therapeutic targets of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. MASLD, metabolic dysfunction-associated steatotic liver disease; MASH, metabolic dysfunction-associated steatohepatitis; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; DKD, diabetic kidney disease; ASCVD, atherosclerotic cardiovascular disease.

Fig. 2.

Fig. 2.

Randomized clinical trials evaluating kidney outcomes of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon- like peptide-1 (GLP-1) receptor agonists in people with chronic kidney disease and diabetes mellitus. CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; EMPA-KIDNEY, Study of Heart and Kidney Protection with Empagliflozin; FLOW, Evaluate Renal Function With Semaglutide Once Weekly; REMODEL, A Research Study to Find Out How Semaglutide Works in the Kidneys Compared to Placebo, in People With Type 2 Diabetes and Chronic Kidney Disease (NCT04865770); nsMRA, nonsteroidal mineralocorticoid receptor antagonist; CONFIDENCE, COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with CKD and type 2 diabetes using a UACR Endpoint (NCT05254002); GIP, glucosedependent insulinotropic polypeptide; DACRA, dual amylin and calcitonin receptor agonist; TREASURE-CKD, A Study of Tirzepatide (LY3298176) in Participants With Overweight or Obesity and Chronic Kidney Disease With or Without Type 2 Diabetes (NCT05536804); Renal Lifecycle, A Randomized Controlled Clinical Trial to Assess the Effect of Dapagliflozin on Renal and Cardiovascular Outcomes in Patients With Severe Chronic Kidney Disease (NCT05374291); TRIUMPH-Outcomes, The Effect of Retatrutide Once Weekly on Cardiovascular Outcomes and Kidney Outcomes in Adults (NCT06383390); PRECIDENTD, PREvention of CardIovascular and DiabEtic kidNey Disease in Type 2 Diabetes (NCT05390892). aPhase 2 randomized clinical trials.

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